The purpose of this COVID-19 research supplement is to critically evaluate if a calcitonin gene-related peptide (CGRP) receptor antagonist can mitigate both neuroinflammatory and hyper-immune responses to SARS-CoV-2 infection. In December 2019, the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) was identified. There are now over ~5.5 million confirmed cases worldwide (1.6 million US), and 345,000 deaths (~100,000 US). COVID-19 causes a respiratory illness like the flu with symptoms such as fever, cough, loss of smell, fatigue, sputum production, shortness of breath, sore throat, headache, chills, and nausea or vomiting. Approximately 80% of people have mild disease and recover. However, in those remaining 20%, COVID-19 is severe and there is evidence that progression to the most serious type of COVID-19 illness is related to a hyper-immune response (ie, cytokine storm). Currently, there are no effective vaccines or treatments available for COVID-19. In this supplement we will test the ability of CGRP-receptor antagonists to inhibit the neuroimmune consequences of SARS-CoV-2 infection, using temperature and nausea as an indicator of SARS-CoV2 infection, as we are doing in our parent grant to assess migraine nausea pain. A humanized mouse model has been developed for studying SARS-CoV2, where mice express the human angiotensin-converting enzyme 2 (hACE2), enabling us to model Covid-19 in the mouse. The FDA has recently approved Biohaven Pharmaceuticals to proceed to a phase 2 clinical trial of its CGRP-receptor antagonist (vazegepant; currently in phase 3 trials for migraine) to treat patients with severe COVID-19, suggesting that the neuroinflammatory reaction that is initiated by CGRP in response to SARS- CoV2 could be a therapeutic target for treating severe Covid-19, and that the non-invasive readouts of neuroinflammation that we are developing could be used to rapidly identify at risk patients. Our hypothesis is that mild to severe COVID-19 symptoms will occur in the transgenic hACE2 mouse that has been infected with SARS-CoV-2, and that a CGRP receptor antagonist will mitigate these symptoms. The specific aims are to test the following hypotheses that transgenic mice and non-carrier littermates infected with SARS-CoV-2 will exhibit: aim 1) mild severe symptoms based on viral load, and if these symptoms are less severe when treated with a CGRP-receptor antagonist; and aim 2) reduced fever and nausea-like pain when treated with a CGRP- receptor antagonist. Information gained from these studies will provide a direct assessment of whether a CGRP-receptor antagonist can mitigate both mild and severe symptoms associated with SARS-CoV-2 infection. This proposal also impacts the development of robust preclinical in vivo assays of COVID-19 symptoms, paving the way to develop and test future therapeutics for COVID-19.